In the majority of the countries in the world, from 15% to 25% of the adult population presents high arterial pressure (MacMahon, S. et al., Blood pressure, stroke, and coronary heart disease, Lancet 335:765-774, 1990). The cardiovascular risk increases with the level of arterial pressure: the higher the arterial pressure, the higher the risk of coronary occurrences. Hypertension, considered to be the main factor responsible for coronary, cerebral and vascular renal diseases, is the number one cause of death and incapacity among adults.
Heart failure is worldwide the main cause of hospitalization in the age group of 60 to 80 years of age. The ageing of the population alone is already a factor for the increase of its incidence: while 1% of the individuals present heart failure between the age of 25 to 54 years, among the elderly the incidence is much higher, reaching the level of 10% to those over 75 years of age (Kannel, W. B. et al., Changing epidemiological features of cardiac failure, Br. Hear J 1994; 72 (suppl 3):S3-S9).
Heart failure, owing to its clinical features, is a limiting disease which, with its aggravation, reduces the quality of life of the patients and, in the most serious cases, presents the characteristics of a malignant disease with a mortality rate of over 60% in the first year, even nowadays (Oliveira, M. T. Clinical features and prognosis of patients with high congested heart failure, College of Medicine USP, 1999). It is estimated that today, in the industrialized world alone, over 15 million people are affected by it and that only in the US, for example, the number of cases has increased 450% between 1973-1990 (Kannel, W. B. et al., Changing epidemiological features of cardiac failure, Br. Hear J 1994; 72 (suppl 3): S3-S9).
Hypertension is complex, multifactorial, of high prevalence, responsible for various deleterious effects and with high morbidity and mortality (Kaplan, N. M. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 275:1571-1576, 1996). With the aim of improving the understanding of the disease, countless studies for the evaluation of the efficiency of its control in the general population and in special groups have been carried out. The control of blood pressure, without a wide non-medicament and/or pharmaceutical intervention in the associated risks factors (diabetes, obesity, tobacco), may reduce substantially the benefits of the long term treatment of arterial hypertension in the decrease of mortality (Wilson, P. W. et al., Hypertension. Raven Press. 94-114).
Hypertension is the pathology that most contributes to cardiovascular arteriosclerosis (The Fifth Report of the Joint National Committee on detection, evaluation, and treatment of High Blood Pressure. National Institute of Health (VJNC). Arch, Intem, Med. 153:154-181, 1994). According to statistics, one in every four americans is or will be hypertensive, and it is estimated that 4.78 millions of people have heart failure. Each year, 400 thousand new cases are diagnosed, giving rise to 800 thousand hospitalizations, with a cost of US$ 17.8 billions of dollars with the treatment.
In Brazil, data from SUS (Sistema Unificado de Saúde) have shown that in 1997, heart failure was the main cause of hospitalizations among the cardiovascular diseases, leading the government to spend R$ 150 million reais with its treatment, a number equivalent to 4.6% of all the expenses with health (Filho, Albanesi F. Heart failure in Brazil. Arq. Bras. Cardiol. 71:561-562, 1998).
The angiotensin II (Ang II), a potent vasoconstrictor, is the most important active hormone of the renin-angiotensin system (RAS) and it makes up an important determinant of the pathophysiology of hypertension. Ang II increases directly and indirectly the peripheral resistance. Directly, it produces vasoconstriction of small arteries and, to a lesser extent, at the level of the post-capillary venules, where a high number of ANGIOTENSIN II AT1 receptors is found. The constriction of the arteries mediated by Ang II increases the vascular resistance, which is a basic hemodynamic mechanism involved in the arterial pressure rise. The constricting intensity is higher in the kidneys and lower in the brain, lungs and in the skeletal muscle. Ang II also leads to the release of aldosterone by the supra-renal gland. The release of the aldosterone increases the blood volume through the increase of sodium and water reabsorption and of the excretion of potassium by the kidneys (Frohlich, E. D., Angiotensin converting enzyme inhibitors. Hypertension 13 (suppl I): 125-130, 1989). It is believed that this increases the arterial pressure in response to the increase of the cardiac output, the second basic hemodynamic mechanism in the rising of arterial pressure. It has been suggested that the release of catecholamines from the supra-renal medulla by Ang II and the stimulation of the release of the norepinefrine by the nerves terminals and the activation of the central nervous system leads to an increase of the sympathetic discharge. (Goodman and Gilman's, The Pharmacological Basis of Therapeutics 8th ed. Pergamon Press, New York, p 755, 1990).
The RAS is an endocrine system in which the renin acts over the angiotensinogen of hepatic origin, to produce angiotensin I in plasma. This peptide is then converted to Ang II, through the action of the angiotensin-converting enzyme (ACE). Thereafter, Ang II is taken to its target organs by the blood flow, binding in a selective way to the ANGIOTENSIN II AT1 receptors (Sasaki, k. et al., Cloning and expression of a complementary DNA enconding a bovine adrenal angiotensin II receptor type-1. Nature, 351:230-233, 1991).
The treatment of hypertension aims not only the reduction of health care expenses, but also the prevention of target organs lesions, through changes in the quality of life and use of medication, when necessary (The Fifth Report of the Joint National Committee on detection, evaluation, and treatment of High Blood Pressure. National Institute of Health (VINC). Arch. Intem. Med.153:154-181,1994).
All the patients with systolic arterial pressure over 180 mmHg or diastolic arterial pressure over 110 mmHg must be submitted to pharmacological treatment, regardless of other present factors or not (Report the Canadian Hypertension Society. Consensus Conference.3. Pharmacologic treatment of essential hypertension. Xan. Med. Assoc. J. 149 (3):575-584, 1993).
Since the 60s, however, the anti-hypertensive drugs became an important tool in the treatment of high arterial pressure (Ménard, J. Anthology of the renin-angiotensin system: A one hundred reference approach to angiotensin II antagonists. J. Hypertension 11 (suppl 3): S3-S11, 1993). During the last four decades, the pharmacological research produced new types of drugs to treat hypertension: the diuretics in the 60s, the betablockers in the 70s, the calcium channel blockers and the angiotensin-converting enzyme inhibitors in the 80s and the ANGIOTENSIN II AT1 receptor antagonists in the 90s.
The ACE inhibitors (ACEI) are capable of inhibiting the conversion of the angiotensin I to Ang II. Thus, the vasoconstricting actions of Ang II are minimized. Preliminary studies showed that teprotide, the first inhibitor used clinically, has an anti-hypertensive action when administered by the intravenous route, however, is inactive by oral route. This fact strongly limited its use.
It is known today that ACE is a multi-action enzyme, which means that it acts on various substrates. Besides acting as a dipeptidase in angiotensin I and in bradykinin, it is capable of hydrolising several peptides, indicating that the enzyme can act in various tissues.
ACEI are excellent when administered in monotherapy. ACEI provokes a relatively fast drop of the arterial pressure in 60 to 70% of the patients with arterial hypertension (Ganong, W. Neuropeptides in cardiovascular control. J. Hypertens 2(suppl 3):1522,1984). They are generally well tolerated, but their use can bring about adverse side effects and reactions, some of which relatively serious, among them, angioneurotic edema and dry cough (8 to 10%).
The first attempt to develop antagonists of Ang II date from the beginning of the 70s and efforts were concentrated on the development of peptides analogous to Ang II, saralasine (1-sarcosina, 8-isoleucine angiotensin II) being the first one. However, these derivatives were not clinically acceptable as they also presented partial agonist activity. In 1982, the two first non-peptide antagonists of ANGIOTENSIN II AT1 receptor were developed (S-8307 and S-8308). However, in spite of being highly specific and without agonist activity, they presented weak binding to the Ang II receptors. With a series of changes in the molecular structure of these two precursors, a new potent product for oral use, and of high specificity was developed, losartan. Since then, many other non-peptide antagonists were developed, such as candesartan, irbersatan, valsartan, telmisartan, eprosartan, tasosartan and zolosartan.
Losartan is a molecule chemically described as a monopotassium salt of 2-butyl-4-cloro-1-[[2′-(1H-tetrazole-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H imidazole-5-ethanol. Its empirical formula is C22H22CIKN6O, a crystal clear powder, white and pale, of free flow and molar mass of 461.01 g/mol. It is rapidly absorbed and it presents a bioavailability of 33% and the peak of maximum concentration is reached within one hour, with an half-life of about two hours. It is soluble in water, soluble in alcohol and slightly soluble in common organic solvents, such as acetonitrile and methyl-ethyl-cetone. Losartan reduces arterial pressure solely by a new, specific and selective mechanism of action: blockade of the Ang II receptor, regardless of the origin or way of production of the Ang II. Losartan does not block other hormone receptors, enzymes or important ionic channels in the cardiovascular regulation.
The oxidation of the 5-hydroxymetyl group in the imidazol ring results in the active metabolite of losartan, designated by EXP-3174. The mechanism of the singular action of losartan can be distinguished from the inhibition of the ACE, by measuring, in the plasma, the induced increase of the renin activity and of Ang II levels (Tavares, Agostinho et al, Antagonists of the Receptors of the Angiotensin II, Pharmacology and Cardiovascular Therapeutics, 305-315, 1998). During the administration of losartan, the renin activity is increased, leading to the increase of the Ang II in the plasma. After the discontinuity of the administration of losartan, the renin activity and the levels Ang II return to the levels of pre-treatment. About 92% of an oral dose of losartan can be detected in the urine and in the feces; 5% are excreted with the losartan, 8% as EXP-3174 and the rest as inactive metabolites (Melntyre, M. et.al. Losartan, an orally active angiotensin ANGIOTENSIN II AT1 receptor antagonist: a review of its efficacy and safety in essential hypertension. Pharmacol. Ther. 74(2):181-194,1997).
Valsartan (1-oxopentyl-N′[[2′-(1H-tetrazole-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-vaniline) is a competitive antagonist of the receptor AT1, presenting bioavailability of 25%, with an half-life of 9 hours, reaching the maximum peak in about 2 hours. It is minimally metabolized and excreted especially through the feces and only 15 to 20% appears in the urine (Criscione, L. de Gasparo et. al. Pharmacological profile of valsartan. Br. J. Pharmacol 110:761-771, 1993). If administered with Atenolol, Cimetidine, Digoxin, Furosemide, it presents pharmacokinetics interactions that enhanced its effect. Irbersartan (2-butyl-3-[[2′-(1H-tetrazole-5-yl)[1,1′biphenyl]4-yl1,3-diazaspirol[4,4]-non-len-4-olone) is a competitive antagonist of the ANGIOTENSIN II AT1 receptor. It is metabolized essentially by oxidation, it presents a peak of concentration between 1.5 and 2 hours and an half-life around 11 to 15 hours (Nisato, D. A review of the new angiotensin II antagonist irbesartan. Cardiovasc Drug Rev). Its availability is of 60 to 80% and it is also excreted mostly by the bile (80%).
Candesartan (2-ethoxy-1-[[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-1H-benzimidazole-7-carboxylic acid), presents high affinity for the ANGIOTENSIN II AT1 receptor and it dissociates slowly, presenting half-life of 9 hours, bioavailability of about 40% and it is eliminated mostly by the urine and the bile (Shibouta, Y. et. al. Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, J. Pharmacol. Exp. Ther. 266:114-120, 1993). When administered together with (nifedipine, digoxina or glibenclamide), it has presented better results.
Eprosartan ((E)-a-[[2-butyl-1-[(4-carboxyphenyl)metyl]-1H-imidazol-5-yl]methylene]-2-thiofenepropanoic acid), has also high affinity for the ANGIOTENSIN II AT1 receptor, with a bioavailability of 13 to 15%, with maximum concentration at about 2 hours. Approximately 90% is eliminated through the feces and the rest in the urine (Ruddy, Michael C. et. al. Angiotensin II Receptor Antagonists. 71:621-633, 1999).
Telmisartan (4′-[(1,4′-dimethyl]-2′propyl[2,6′-bi1H-benzimidazole]-1′-yl)methyl]1,1′biphenyl]-2-carboxilic acid) is a competitive inhibitor of the ANGIOTENSIN II AT1 receptor and presents a bioavailability of 45%. It is excreted mostly by the bile (97%) (Ruddy, Michael C. et. al. Angiotensin II Receptor Antagonists. 71:621-633, 1999).
The angiotensin-(1-7), (Asp-Arg-Val-Tyr-Ile-H is Pro), and its derivative Sar1-Ang-(1-7) also antagonize the pressure effect of the Ang II in human beings (Ueda et al., Mol. Biol. Cell 11:259A-260A suppl. S December 2000) and rats. The contraction produced by Ang II in isolated arteries of rabbits and humans is also reduced by the angiotensin-(1-7) (Roks et al. Eur. Heart J 22:53-53 Suppl. S Sep, 2001).
U.S. Pat. No. 4,340,598 (CA1152515, JP56071073, EP0028833, DE3066313D), Yoshiyasu, Toyonara et al. (1982) have developed a method to obtain new anti-hypertensive compounds through the substitution of the imidazol ring by phenyl, halogen, nitro or amino groups, in order to obtain imidazol derivatives. These compounds presented an excellent antagonist activity for the ANGIOTENSIN II AT1 receptor, being utilized as hypotensive agents.
U.S. Pat. Nos. 4,576,958 (4,372,964), Wexler, Ruth R. (1986), has also developed some derivatives of the 4,5-diaryl-1H-imidazol-2-methanol, which presented anti-hypertensive effect, because of their vasodilating properties. This finding was based on a series of chemical reactions, among them, Friedel-Crafts acylation, reflux in formamide and oxidation.
U.S. Pat. No. 4,598,070 (CA1215359, DK 356684, EP135044, ES8506757, GR82322, JP60025967), Mashiro, Kawahara et al. (1986), have developed an invention based on the preparation of inclusion compounds between the anti-hypertensive agent, Tripamide, and cyclodextrins (cyclodextrin and cyclodextrin). The use of cyclodextrin resulted in the improvement of the solubility of tripamide.
U.S. Pat. No. 4,666,705, de Crosta, Mark. T. et al. (1987) have proposed a new drug-controlled release system for the treatment of hypertension. An inhibitor of ACE, the Captopril, was used because its fast absorption, with half-life of two hours. In order to prolong its presence in the organism, Captopril was associated to polymer or co-polymer in the form of tablets. The polymer utilized was the (polyvinyl pirrolidone) (PVP) and the technique used was the dry granulation. As a result, the drug permanence was increased from 4 to 16 hours.
U.S. Pat. No. 5,064,825, Chakravarty, Prasun, K. et al. (1991), have obtained new derivatives of the imidazol ring, presenting seven member-rings and showing antagonist activity for the ANGIOTENSIN II AT1 receptor.
U.S. Pat. No. 5,073,641, Bundgaard, Hans et al. (1991), have obtained new ester derivatives of the carboxylic acid as inhibitors to the ACE. Among them, the ethyl-ester, Pentopril, was found to be highly stable in the human plasma.
U.S. Pat. No. 5,171,748 (JP3005464, CA2017065, EP0399732), Roberts, David et al. (1992), have also obtained new heterocyclics derivatives of the imidazol ring, which antagonize the action of angiotensin II.
U.S. Pat. No. 5,256,687, Becker, Reinhard et. al. (1993), have claimed a pharmaceutical composition, consisting of an inhibitor of the ACE (Tandolpril or Pamipril) associated to a diuretic (Furosemide or Piretamide), and its use in the treatment of hypertension, this way increasing the efficiency of the ACE inhibitors.
U.S. Pat. No. 5,266,583, Otawa, Masakatsu (1993), have isolated a metabolite of the Losartan, which presented an antagonist activity for the ANGIOTENSIN II AT1 receptor.
U.S. Pat. No. 5,519,012, Fercej-Temeljoov, Darja et. al. (1996), have claimed a new inclusion compound for the anti-hipertensive agent, 1,4-dihydropiridine, with methyl-p-cyclodextrin and other derivatives such as cyclodextrin hydroxilate.
U.S. Pat. No. 5,728,402, Chen, Chih-Ming et al. (1998), have claimed the preparation and use of a pharmaceutical composition containing an internal phase, composed by Captopril (ACE inhibitor) and an hydrogel, and an external phase insoluble in the stomach. This formulation resulted in the increase of the duration of drug absorption.
U.S. Pat. No. 5,834,432, (AU5990796, CA2221730, EP0828505, WO09639164, JP115073625), Rodgers, Kathlen Elizabeth et al. (1998), utilized agonists of the AT2 receptors to improve wound healing.
U.S. Pat. No. 5,859,258 (HR970565, CN124186, SK57099, EP0937068, AU5089898), Breen, Patrick et al. (1999), have developed a process for crystallizing the ANGIOTENSIN II AT1 receptor antagonist, Losartan through the addition of solvents (among them, isopropanol, water, cyclohexane) and followed by the distillation.
AU200012728-A, Anker, S D and Cats, Aj. S. (1999), have developed a new derivative of the imidazol ring, more efficient than Losartan when administered orally.
WO9916437, Remuzzi, Giuseppe (1999), have developed a new imidazol derivative. The resulting drug was capable of increasing the survival of patients with renal and cardiac transplants.
WO0110851, Galbiat Bárbara Via Goldomi (1999) et. al have developed a process for the preparation of lysine-carboxyanidride, an intermediate product in the synthesis of the Lisonopril.
WO0037075, Synthelabo, Elizabeth Sanofi et. al. (1999) claimed the use of a combination of an ANGIOTENSIN II AT1-receptor antagonist (Irbesartan) and an immunosupressor (cyclosporin). This combination was found to be efficient in the treatment of cardiovascular problems.
U.S. Pat. No. 6,087,386 (WO9749392A1) Chen, Tzyy-Show H. et al. (2000) claimed the preparation an use of a pharmaceutical containing one layer of Losartan (ANGIOTENSIN II AT1 receptor antagonist) and the other layer of maleate de enalapril (ACE inhibitor). This formulation resulted in the improvement of the pharmacological action, decreasing the side effects and prolonging the absorption.
U.S. Pat. No. 6,096,772 (AU1184097, AU706660, CA2225175, HU9901448, CN1192681, JP11507921T, ZA9604690), Fandriks, Lars et al utilized ANGIOTENSIN II AT1 receptor antagonists for the treatment or prophylaxis of dispeptidic symptoms.
U.S. Pat. No. 6,178,349, Kieval, Roberts S. et al. (2001) have developed a device based on the release of the drug via neural stimulation for the treatment of cardiovascular diseases. This device consists of an eletrode connected to the nerve, an implantable pulse generator and a reservoir which contains the drug to be applied. During the use, the electrode and the release of the medicine stimulate the nerve, which affects the control over the cardiovascular system.